We propose to examine four inter-related pathogenic pathways for prostate carcinogenesis: the vitamin D axis, inflammation, sex steroids, and insulin/insulin-like growth factor signaling. We hypothesize that many of the proposed modifiable factors for prostate cancer (intakes of vitamin D, calcium, milk, antioxidants, n-3 fatty acids, polyunsaturated fat, hyperinsulinemic diets, obesity, anti-inflammatory agents) may operate through these pathways. A better understanding of how modifiable risk factors in conjunction with genetic susceptibility operate through these mechanisms can help optimize preventive strategies for prostate cancer. In addition, prostate cancers exhibit a profound range of heterogeneity in biologic potential for progression among tumors. We hypothesize that this heterogeneity is related to acquired molecular characteristics in the tumor. Thus, we will additionally examine dietary and hormonal factors that are identified to be related to aggressive behavior in prostate cancer in relation to specific molecular characteristics that determine biologic aggressive potential, such as differentiation and angiogenesis. In addition, we will examine whether identified dietary and other modifiable risk factors can, in the post-diagnostic period, influence survival among men treated with prostatectomy for apparently organ-confined prostate cancer. To accomplish our aims to dietary, hormonal, and genetic factors related to prostate cancer incidence and progression, we will use data in the Health Professionals Follow-up Study (HPFS), a cohort of the 47,000 men free of cancer at baseline in 1986. We project 5,502 new cases of prostate cancer by 2008, including 579 fatal cases, with tumor blocks from over 1,700 prostatectomy cases. The sources of the exposure data in the HPFS are (1) questionnaire, including diet, anthropometric measures, activity, medication use, (2) plasma samples, and (3) DMA. The outcome data will be based on (1) medical record and pathology report review for initial diagnosis and survival, and (2) tissue block markers that correlated with disease progression. We will use multivariate analysis to control for confounding factors. This project is likely to yield important new findings that may help our understanding of modifiable risk factors for prostate cancer incidence, progression, and survival. Our ultimate goal is to better understand how dietary and other modifiable factors, including widely used medications such as aspirin and statins, influence prostate carcinogenesis at various stages, including after diagnosis, and to identify the susceptible men who would be most likely to benefit from specific dietary and lifestyle changes.